The Positive Effects of ARBs on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy

Abstracts & Commentary

Synopsis: ARBs are associated with significant renal benefits independent of their blood pressure lowering effects.

Sources: Brenner BM, et al. N Engl J Med. 2001;345: 861-869; Lewis EJ, et al. N Engl J Med. 2001;345:851-860; Parving HH, et al. N Engl J Med. 2001;345:870-878.

Yusuf and colleagues clearly demonstrated that the ACE inhibitor ramipril significantly reduced the risk of death, myocardial infarction, and stroke in a broad range of high-risk patients who were known not to have a low ejection fraction or heart failure.1 A substudy of that trial known as the MICRO-HOPE revealed that ramipril provided protection against cardiovascular events and attenuated the increase in proteinuria commonly observed in patients with type 2 diabetes and microalbuminuria.2

Recognizing that diabetic nephropathy is the leading cause of end-stage renal disease and that interruption of the renin-angiotensin system has been demonstrated to slow the progression in patients with type 2 diabetes, Brenner and associates for the RENAAL Study investigators studied the effects of using an angiotensin-receptor blocking agent (losartan) on renal function in a total of 1513 patients enrolled in a multicenter, randomized, double-blind study. Losartan was added to conventional antihypertensive therapy and compared to a placebo for a mean of 3.4 years. Losartan was found to confer significant renal benefits in patients with type 2 diabetes and nephropathy by significantly reducing the incidence of: 1) a doubling of the serum creatinine concentration, and 2) end-stage renal disease; but, it was found to have no effect upon the death rate.

In the same issue of the New England Journal of Medicine, Lewis and colleagues for the Collaborative Study Group reported on the ability of an angiotensin-receptor blocker (irbesartan) and a calcium-channel blocker (amlodipine) to slow the progression of nephropathy in patients with type 2 diabetes independent of the capacity of these agents to lower the systemic blood pressure. This multicenter study followed patients for 2.6 years and found that treatment with irbesartan resulted in a 20% lower incidence than the placebo group and a 23% lower incidence than the amlodipine group with respect to: 1) the doubling of the base-line serum creatinine concentration; 2) the development of end-stage renal disease; or 3) death from any cause. They concluded that irbesartan was effective in protecting against the progression of nephropathy due to type 2 diabetes independent of any reduction in blood pressure that it may cause.

Finally, a third article in the same journal by Parving and colleagues reporting for the Microalbuminuria Study Group also found that irbesartan was renal protective independent of its blood pressure-lowering effect in patients with type 2 diabetes and microalbuminuria. This multinational, randomized, double-blind, placebo-controlled study was performed on 590 hypertensive patients who were carefully followed for 2 years.

Comment by Harold L. Karpman, MD, FACC, FACP

Nephropathy due to Type 2 diabetes resulted in 90,000 cases of chronic renal failure in the United States over the past year. More than 300,000 patients are now being treated by dialysis and 80,000 more have been subjected to kidney transplants. Glycemic and blood pressure control and blockade of the renin-angiotensin-aldosterone system all appear to be of special value in slowing or eliminating the occurrence of nephropathy secondary to type 2 diabetes. ACE inhibitors have clearly been demonstrated to provide protection for diabetics against cardiovascular events and have attenuated the increase observed in proteinuria in these subjects2 and now we have convincing evidence that angiotensin-receptor blocking agents (ie, losartan and irbesartan) are also capable of conferring significant renal benefits in patients with type 2 diabetes.4

Unfortunately, patients at high risk for diabetic nephropathy are rarely identified early, which may explain why diabetes remains the single most important cause of end-stage renal disease in Europe, Japan, and the United States. It is, therefore, particularly important to determine the presence or absence of early diabetic nephropathy in patients with type 2 diabetes by determining whether albuminuria is present, even in patients with acceptable glycemic control, since ACE inhibitors and angiotensin-receptor blockers have now been clearly demonstrated to lower the levels of proteinuria, to decrease the rate of decline in the glomerular filtration rate, and to delay the onset of end-stage renal disease. One analysis has even suggested that an ACE inhibitor would be cost effective if prescribed for all middle-aged patients with type 2 diabetes irrespective of their base-line renal status and, although angiotensin-receptor blockers are somewhat more expensive, the same conclusions probably would hold for this class of drugs.6 The findings of Brenner et al confirmed the results of other studies by demonstrating that angiotensin-receptor blockers lower levels of proteinuria, diminish the rate of decline in the glomerular filtration rate, and delay the onset of end-stage renal disease even in patients with well advanced renal disease.

The final detailed prospective outcome studies have not yet been performed to determine whether ACE inhibitors are better than angiotensin-receptor blockers or vice-versa; however, it now appears likely that these agents are similar with respect to their ability to diminish proteinuria and to provide protection from progressive renal damage. Therefore, type 2 diabetic patients who are initially treated with ACE inhibitors and who develop symptomatic complications such as a troubling cough should be switched to angiotensin-receptor blockers since these agents now appear to provide a similar degree of renal protection.

There now seems to be little question that ACE inhibitors and angiotensin-receptor blockers do indeed provide a significant degree of renal protection in diabetics and it would, therefore, appear that clinicians should consider prescribing one or the other to all middle-aged or older patients with type 2 diabetes irrespective of their baseline renal status.

References

1. Yusuf S, et al. N Engl J Med. 2000;342:145-153.

2. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355:253-259. (Published erratum appears in Lancet. 2000;356:860).

3. Golan L, et al. Ann Intern Med. 1999;131:660-667.

4. Parving HH, Osterby R, Ritz E. Diabetic nephropathy. In: Brenner BM, ed. The Kidney. 6th ed. Pa, WB Saunders; 2000:1731-1773.

Dr. Karpman, Clinical Professor of Medicine, UCLA School of Medicine, is Associate Editor of Internal Medicine Alert.